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PHF2 Histone Demethylase Prevents DNA Damage and Genome Instability by Controlling Cell Cycle Progression of Neural Progenitors

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PHF2 Histone Demethylase Prevents DNA Damage and Genome Instability by Controlling Cell Cycle Progression of Neural Progenitors PHF2 histone demethylase prevents DNA damage and genome instability by controlling cell cycle progression of neural progenitors Stella Pappaa, Natalia Padillab,c,1, Simona Iacobuccia,1, Marta Viciosoa, Elena Álvarez de la Campab,c, Claudia Navarroa, Elia Marcosa, Xavier de la Cruzb,c,2, and Marian A. Martínez-Balbása,2 aDepartment of Molecular Genomics, Instituto de Biología Molecular de Barcelona, Consejo Superior de Investigaciones Científicas, 08028 Barcelona, Spain; bClinical and Translational Bioinformatics, Vall d’Hebron Institute of Research, E-08035 Barcelona, Spain; and cInstitut Català per la Recerca i Estudis Avançats, 08018 Barcelona, Spain Edited by Robert E. Kingston, Massachusetts General Hospital/Harvard Medical School, Boston, MA, and approved August 6, 2019 (received for review February 25, 2019) Histone H3 lysine 9 methylation (H3K9me) is essential for cellular terestingly, PHF2 mutations have been found in patients with homeostasis; however, its contribution to development is not well autism spectrum disorder (ASD) (22–24). Despite PHF2 high established. Here, we demonstrate that the H3K9me2 demethy- expression in the neural tube and its implication on mental dis- lase PHF2 is essential for neural progenitor proliferation in vitro eases, PHF2 involvement in neural development has not yet and for early neurogenesis in the chicken spinal cord. Using genome- been explored. wide analyses and biochemical assays we show that PHF2 controls In this study, we analyzed the role of PHF2 in neural stem cell the expression of critical cell cycle progression genes, particularly (NSC) biology. We found that PHF2 is essential for progenitor those related to DNA replication, by keeping low levels of H3K9me3 proliferation in vitro and in vivo, in the chicken spinal cord. at promoters. Accordingly, PHF2 depletion induces R-loop accu- PHF2 binds and regulates cell cycle gene promoters, particularly mulation that leads to extensive DNA damage and cell cycle arrest. These data reveal a role of PHF2 as a guarantor of genome stabil- those involved in DNA replication and cell cycle progression. ity that allows proper expansion of neural progenitors during Moreover, PHF2 depletion induces R-loop accumulation, DNA development. damage, and cell cycle arrest. These data reveal a role for PHF2 as a safeguard of genome stability during development. histone demethylation | chromatin transcription | neuronal progenitor Results proliferation | PHF2 PHF2 Binds Promoters and Mediates H3K9me2 Demethylation. To uring neural development, multipotent progenitor cells self- gain insight into the biological substrate of PHF2 in NSCs, we Drenew and ultimately originate specialized neurons and glial performed chromatin immunoprecipitation coupled with sequencing cells (1, 2). The chromatin acting factors are essential players in both proliferation and cell differentiation events during embryo Significance development. This epigenetic regulation is achieved by stabiliz- ing chromatin structure that allows establishing heritable gene During early neurogenesis, progenitors maintain the balance expression patterns. The epigenetic control is mainly mediated between self-renewal and differentiation. This equilibrium is by covalent modifications of histones and DNA (3). Recently, preserved by the coordinated action of developmental cues histone methylation/demethylation has received special attention and epigenetic mechanisms. We analyzed the role of the as an essential regulator of gene expression and genome stability H3K9me2 histone demethylase PHF2 in neural stem cells bi- during development (4). One critical histone modification during ology in vitro and in early neurogenesis in the chicken neural development is dimethylation of histone H3 at lysine 9 (H3K9me2), tube. We found that PHF2 is essential for proliferation of pro- implicated in the silencing of genes playing important roles in genitors. Additionally, PHF2 maintains the genome integrity, chromatin homeostasis and development (5). In embryonic preventing R-loop accumulation and DNA damage. Our work stem (ES) cells, it has been proposed that H3K9me2 increases contributes to the clarification of both the physiological and across the genome as cells differentiate and acquire lineage molecular roles of PHF2 during early neurogenesis. It opens specificity (6), although this is contentious (7). In addition, avenues to understand the role of H3K9 methylation not only H3K9me2 together with H3K9me3 are essential components of in development but also in diseases such as autism, cancer, and the constitutive heterochromatin (8–10). obesity where PHF2 has been involved. Despite the importance of this modification during develop- ment, little is known about the role of the enzymes responsible Author contributions: S.P., X.d.l.C., and M.A.M.-B. designed research; S.P., S.I., M.V., C.N., and E.M. performed research; X.d.l.C. and M.A.M.-B. contributed new reagents/analytic for this mark in neurogenesis. PHF2 is a member of the KDM7 tools; S.P., N.P., S.I., M.V., E.Á.d.l.C., C.N., E.M., X.d.l.C., and M.A.M.-B. analyzed data; and histone demethylase (HDM) family (11). It contains a plant home- M.A.M.-B. wrote the paper. odomain (PHD) in the N-terminal and the Jumonji-C (JMJC) do- The authors declare no conflict of interest. main, which has demethylase enzymatic activity (12). Biochemical This article is a PNAS Direct Submission. studies demonstrated that PHF2 demethylates H3K9me2 upon Published under the PNAS license. interaction with H3K4me2/3 through its PHD domain (13). Data deposition: RNA-seq and ChIP-seq data have been deposited in the GEO database PHF2 was first identified as a candidate gene for hereditary sen- under accessions GSE122264 and GSE122263, respectively. sory neuropathy type I (14) because it is expressed at high levels in 1N.P. and S.I. contributed equally to this work. the neural tube and dorsal root ganglia (15). The physiological 2To whom correspondence may be addressed. Email: [email protected] or mmbbmc@ role of PHF2 in vivo is not yet clear, but it is a coactivator of ibmb.csic.es. multiple transcription factors (11). Working with them, PHF2 This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. regulates various differentiation processes (16–18). Alterations in 1073/pnas.1903188116/-/DCSupplemental. PHF2 have been identified in several cancer types (19–21). In- First published September 5, 2019. 19464–19473 | PNAS | September 24, 2019 | vol. 116 | no. 39 www.pnas.org/cgi/doi/10.1073/pnas.1903188116 Downloaded by guest on September 29, 2021 (ChIP-seq) experiment. We detected 5,992 peaks normalized to research tool. We identified as the top 3: Homez, YY2, and the input (P value of 1e-10) in ChIP data for PHF2. SI Appendix, E2F4 DNA binding motifs (Fig. 1E). These transcription factors, Fig. S1A shows validation of ChIP-seq results by qPCR for a ran- particularly E2F4 and YY2, are essential to control progenitor dom set of PHF2 targets. Then, we examined the genomic distri- self-renewal and cell cycle progression (26–28), suggesting a po- bution of the PHF2 peaks. Our results showed that 97% of PHF2 tential role of PHF2 in cell proliferation. To reinforce these data, peaks localized on gene promoters, around the transcription start we analyzed the colocalization of PHF2 and E2F4 using pre- site (TSS) (Fig. 1A), as it has been reported in a different cellular viously published ChIP-seq data in HeLa S3 cells. The results context (25). showed that the 50.3% (P value <2.2e-16) of E2F4-bound re- It has been proposed that PHF2 through its PHD domain gions, respectively, also contained PHF2 (Fig. 1F). These results interacts with H3K4me2/3 histone marks; thus, we analyzed the reveal a potential role of PHF2 in regulating E2F-mediated colocalization of PHF2 and H3K4me2/3 at the genome-wide transcription as it has been described for another KDM7 family level using previously published H3K4me2/3 ChIP-seq data from member, PHF8 (29). Accordingly, gene ontology (GO) analysis of NSCs. Doing that, we identified 5,978 (99.7%) (P value <2.2e-16) PHF2-bound regions indicated that PHF2 was associated with the and 5,983 (99.8%) (P value <2.2e-16) PHF2-bound regions promoter region of genes involved in cell cycle regulation, DNA that also contained H3K4me3 or H3K4me2, respectively (Figs. 1 repair, RNA processing, and chromatin organization, among B–D and 2B and SI Appendix,Fig.S1B). The high overlapping others (Fig. 1G). suggests a required H3K4me2/3 mark for effective PHF2 binding Previous studies demonstrated that PHF2 demethylates mainly at promoters as it is described (13, 25). To better understand H3K9me2 (13, 25). We thus analyzed the distribution of H3K9me2 how PHF2 is targeted to the chromatin, we performed bio- in NSCs by performing ChIP-seq experiments and compared it informatics analysis that revealed the most statistically significant with PHF2 genomic-associated regions. As expected for a H3K9me2 predicted PHF2 binding sites using the Homer de novo motif demethylase, the vast majority (99.99%) (P value <2.3e-6) of BIOCHEMISTRY Fig. 1. PHF2 binds promoters in NSCs. (A) Genomic distribution of PHF2 ChIP-seq peaks in NSCs showing that PHF2 mainly binds promoter regions around the TSS. (B) Heatmaps depicting PHF2 binding to H3K4me3- and H3K4me2-marked promoters in NSCs 3 kb around the TSS. Scales indicate ChIP-seq intensities. (C)Venn diagrams showing overlap between PHF2-bound and H3K4me3 and H3K4me2-marked regions. P value is the result of an equal proportions test performed between H3K4me3 and H3K4me2 peaks and a random set. (D) IGV capture showing PHF2, H3K4me3, and H3K4me2 peaks in E2f3 gene in NSCs. (E) Motif enrichment analysis of PHF2 ChIP-seq peaks in NSCs using the Homer de novo motif research tool showing the 3 top enriched motifs. (F) Heatmap representation of PHF2 and E2F4 co- occupied regions (Left) and Venn diagrams (Right) showing peak overlapping between PHF2-bound and E2F4-bound regions in published ChIP-seq in HeLa S3 cells.
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